EP2250163B1 - Inhibiteurs du virus de l'hépatite c - Google Patents

Inhibiteurs du virus de l'hépatite c Download PDF

Info

Publication number
EP2250163B1
EP2250163B1 EP08780411A EP08780411A EP2250163B1 EP 2250163 B1 EP2250163 B1 EP 2250163B1 EP 08780411 A EP08780411 A EP 08780411A EP 08780411 A EP08780411 A EP 08780411A EP 2250163 B1 EP2250163 B1 EP 2250163B1
Authority
EP
European Patent Office
Prior art keywords
methyl
hcv
imidazol
compound
diyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP08780411A
Other languages
German (de)
English (en)
Other versions
EP2250163A1 (fr
Inventor
Carol Bachand
Makonen Belema
Daniel H. Deon
Andrew C. Good
Jason Goodrich
Clint A. James
Rico Lavoie
Omar D. Lopez
Alain Martel
Nicholas A. Meanwell
Van N. Nguyen
Jeffrey Lee Romine
Edward H. Ruediger
Lawrence B. Snyder
Denis R. St. Laurent
Fukang Yang
David R. Langley
Gan Wang
Lawrence G. Hamann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to SI200830675T priority Critical patent/SI2250163T1/sl
Priority to PL08780411T priority patent/PL2250163T3/pl
Publication of EP2250163A1 publication Critical patent/EP2250163A1/fr
Application granted granted Critical
Publication of EP2250163B1 publication Critical patent/EP2250163B1/fr
Priority to CY20121100523T priority patent/CY1112848T1/el
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present disclosure is generally directed to antiviral compounds, and more specifically directed to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS5A protein.
  • HCV Hepatitis C virus
  • HCV is a major human pathogen, infecting an estimated 170 million persons worldwide - roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma.
  • HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5' untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
  • the single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NSSA, and NS5B) is effected by two viral proteases.
  • ORF open reading frame
  • the first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to herein as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites.
  • the NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
  • NS5B (also referred to herein as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV.
  • HCV NS5A protein is described, for example, in Tan, S.-L., Katzel, M.G. Virology 2001, 284, 1-12 ; and in Park, K.-J.; Choi, S.-H, J. Biological Chemistry 2003 . WO 2006/133326 describes HCV inhibitor.
  • the present disclosure provides a compound selected from dimethyl (4,4'-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S)-1-oxo-1,2-propanediyl)))biscarbamate dimethyl (4,4'-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-meth-1,1-propanediyl)imino((2S,3R)-3-methoxy-1-oxo-1,2-butanediyl)))biscarbamate; dimethyl (4,4'-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((2S)-3-methyl-1-oxo
  • the present disclosure provides a compound of (II) selected from or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the composition comprises one or two additional compounds having anti-HCV activity.
  • at least one of the additional compounds is an interferon or a ribavirin.
  • the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.
  • the present disclosure provides a composition
  • a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or two additional compounds having anti-HCV activity, wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type I helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • the present disclosure provides a composition
  • a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or two additional compounds having anti-HCV activity, wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.
  • a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.
  • the present disclosure provides a compound of the invention for use in a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the method further comprises administering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the compound of the invention, or a pharmaceutically acceptable salt thereof.
  • at least one of the additional compounds is an interferon or a ribavirin.
  • the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.
  • the present disclosure provides a compound of the invention for use in a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof and adminstering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the compound of the invention, or a pharmaceutically acceptable salt thereof, wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • the present disclosure provides a compound of the invention for use in a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof and adminstering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the compound of the invention, or a pharmaceutically acceptable salt thereof, wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B portein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.
  • a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B portein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and
  • the compounds of the present disclosure also exist as tautomers; therefore the present disclosure also encompasses all tautomeric forms.
  • R 8 may be attached to either the carbon atom in the imidazole ring or, alternatively, R 8 may take the place of the hydrogen atom on the nitrogen ring to form an N-substituted imidazole.
  • Certain compounds of the present disclosure may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present disclosure includes each conformational isomer of these compounds and mixtures thereof.
  • the compounds of the present disclosure can exist as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt represents salts or zwitterionic forms of the compounds of the present disclosure which are water or oil-soluble or dispersible, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate; digluconate, dihydrobromide, diydrochloride, dihydroiodide, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichlor
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, and N,N'-dibenzylethylenediamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • compositions which include therapeutically effective amounts of compounds of the invention or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • therapeutically effective amount refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., a reduction in viral load. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
  • the compounds of the invention and pharmaceutically acceptable salts thereof are as described above.
  • the carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the invention, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of between about 0.01 and about 250 milligram per kilogram (“mg/kg”) body weight per day, preferably between about 0.05 and about 100 mg/kg body weight per day of the compounds of the present disclosure are typical in a monotherapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • mg/kg milligram per kilogram
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Treatment may be initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
  • compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent
  • both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection are preferred.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt and/or
  • absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac,
  • Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.
  • the compounds of the invention, and pharmaceutically acceptable salts thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phopholipids, such as cholesterol, stearylamine, or phophatidylcholines.
  • the compounds of the invention and pharmaceutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research 1986, 3(6), 318 .
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and soutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • patient includes both human and other mammals.
  • treating refers to: (i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (iii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition.
  • the compounds of the present disclosure can also be administered with a cyclosporin, for example, cyclosporin A.
  • Cyclosporin A has been shown to be active against HCV in clinical trials ( Hepatology 2003, 38, 1282 ; Biochem. Biophys. Res. Commun. 2004, 313, 42 ; J. Gastroenterol. 2003, 38, 567 ).
  • Table 1 below lists some illustrative examples of compounds that can be administered with the compounds of this disclosure.
  • the compounds of the disclosure can be administered with other anti-HCV activity compounds in combination therapy, either jointly or separately, or by combining the compounds into a composition.
  • Table 1 Brand Name Physiological Class Type of Inhibitor or Target Source Company NIM811 Cyclophilin Inhibitor Novartis Zadaxin Immunomodulator Sciclone Suvus Methylene blue Bioenvision Actilon (CPG10101) TLR9 agonist Coley Batabulin (T67) Anticancer ⁇ -tubulin inhibitor Tularik Inc., South San Francisco, CA ISIS 14803 Antiviral antisense ISIS Pharmaceutica ls Inc, Carlsbad, CA/Elan Pharmaceutical s Inc., New York, NY Summetrel Antiviral antiviral Endo Pharmaceutica ls Holdings Inc., Chadds Ford, PA GS-9132 (ACH-806) Antiviral HCV Inhibitor Achillion
  • the compounds of the present disclosure may also be used as laboratory reagents.
  • Compounds may be instrumental in providing research tools for designing of viral replication assays, validation of animal assay systems and structural biology studies to further enhance knowledge of the HCV disease mechanisms. Further, the compounds of the present disclosure are useful in establishing or determining the binding site of other antiviral compounds, for example, by competitive inhibition.
  • the compounds of this disclosure may also be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of laboratory or medical personnel or patients who come in contact with such materials, e.g., blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection or transfusion apparatuses and materials.
  • materials e.g., blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection or transfusion apparatuses and materials.
  • This disclosure is intended to encompass compounds of the invention when prepared by synthetic processes or by metabolic processes including those occurring in the human or animal body ( in vivo ) or processes occurring in vitro .
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Boc or BOC for tert-butoxycarbonyl
  • NBS for N-bromosuccinimide
  • tBu or t-Bu for tert-butyl
  • SEM for-(trimethylsilyl)ethoxymethyl
  • DMSO for dimethylsulfoxide
  • MeOH for methanol
  • TFA trifluoroacetic acid
  • RT room temperature or retention time (context will dictate); t R for retention time
  • EDCI for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DMAP for 4-dimethylaminopyridine
  • ketoamide 1a (12.8 g, 31.12 mmol) and NH 4 OAc (12.0 g, 155.7 mmol) in xylenes (155 mL) was heated in a sealed tube at 140°C for 2 hours.
  • the volatile component was removed in vacuo , and the residue was partitioned carefully between ethyl acetate and water, whereby enough saturated NaHCO 3 solution was added so as to make the pH of the aqueous phase slightly basic after the shaking of the biphasic system.
  • the layers were separated, and the aqueous layer was extracted with an additional ethyl acetate.
  • the combined organic phase was washed with brine, dried (MgSO 4 ), filtered, and concentrated in vacuo .
  • the resulting material was recrystallized from ethyl acetate/hexanes to provide two crops of imidazole 1b as a light-yellow dense solid, weighing 5.85 g.
  • the mother liquor was concentrated in vacuo and submitted to a flash chromatography (silica gel; 30% ethyl acetate/hexanes) to provide an additional 2.23 g of imidazole 1b.
  • Pd(Ph 3 P) 4 (469 mg, 0.406 mmol) was added to a pressure tube containing a mixture of bromide 1b (4.008 g, 10.22 mmol), bis(pinacolato)diboron (5.422 g, 21.35 mmol), potassium acetate (2.573g, 26.21 mmol) and 1,4-dioxane (80 mL).
  • the reaction flask was purged with nitrogen, capped and heated with an oil bath at 80°C for 16.5 hours.
  • the reaction mixture was filtered and the filtrate was concentrated in vacuo .
  • the crude material was partitioned carefully between CH 2 Cl 2 (150 mL) and an aqueous medium (50 mL water + 10 mL saturated NaHCO 3 solution). The aqueous layer was extracted with CH 2 Cl 2 , and the combined organic phase was dried (MgSO 4 ), filtered, and concentrated in vacuo .
  • the resulting material was purified with flash chromatography (sample was loaded with eluting solvent; 20-35% ethyl acetate/CH 2 Cl 2 ) to provide boronate 1c, contaminated with pinacol, as an off-white dense solid; the relative mole ratio of 1c to pinacol was about 10:1 ( 1 H NMR). The sample weighed 3.925 g after ⁇ 2.5 days exposure to high vacuum.
  • PdCl 2 (Ph 3 P) 2 (257 mg, 0.367 mmol) was added to a dioxane (45 mL) solution of 1-bromo-4-iodo-2-methylbenzene (3.01 g, 10.13 mmol) and tri-n-butyl(1-ethoxyvinyl)stannane (3.826 g, 10.59 mmol) and heated at 80°C for ⁇ 17 hours.
  • the reaction mixture was treated with water (15 mL), cooled to -0 °C (ice/water), and then NBS (1.839 g, 10.3 mmol) was added in batches over 7 minutes.
  • LC/MS Anal. Calcd. for [M+Na] + C 19 H 24 BrNNaO 5 448.07; found 448.10. Additional keto-esters can be prepared in analogous fashion.
  • Example R5 dimethyl (4,4'-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino((1S)-1-oxo-1,2-propanediyl)))biscarbamate
  • Example Compound Name Structure Analytical Data Example R6 dimethyl (4,4'-biphenyldiylbis(1H-imidazole-4,2-diyl((1S)-2-methyl-1,1-propanediyl)imino(( 2S,3R)-3-methoxy-1-oxo-1,2-butanediyl)))biscarb amate LCMS: Anal. Calcd. for C 40 H 54 N 8 O 8 : 774; found: 775 (M+H) + .
  • Example R14 dimethyl (4,4'-biphenyldiylbis(1H-imidazole-4,2-diyl((1 S)-2-methyl-1,1-propanediyl)imino(( 2R)-3-methyl-1-oxo-1,2-butanediyl)))biscarb amate Anal. Calcd. for C 40 H 54 N 8 O 6 : 742; found: 743 (M+H) + .
  • Tetrakis(triphenylphosphine)palladium(0) (0.293 g, 0.254 mmol) was added and the the reaction mixture was heated overnight at 100°C. The mixture was cooled to rt and the DME was removed in vacuo. The residue was partitioned between H 2 O and EtOAc and the layers separated. The aq phase was extracted with EtOAc and the combined organic layers were concentrated to dryness in vacuo and purified purified by column chromatography (Biotage) eluting with a gradient of 0 to 40% CH 3 CN in CH 2 Cl 2 and then 0 to 10% MeOH in CH 2 Cl 2 . The title compound (2.05 g, 65 % yield) was obtained as a brown foam. This material was used as is in subsequent steps. LCMS: Anal. Calcd. for C 36 H 46 N 6 O 4 :626; found: 627 (M+H) + .
  • Example R18 N 2 -(methoxycarbonyl)-N-((1S)-1-(4-(4'-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-2-methylpropyl)-L-valinamide
  • Example R23 methyl ((1S,2R)-2-methoxy-1-(((2S)-2-(4-(4'-(2-((1R)-1-((N-(methoxycarbonyl)-O-methyl-L-threonyl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl) propyl)carbamate LCMS: Anal. Calcd. for C 40 H 52 N 8 O 8 : 772 found: 773 (M+H) + .
  • Example R24 methyl ((1S)-3-methoxy-1-(((2S)-2-(4-(4'-(2-((1R)-1-((N-(methoxycarbonyl)-O-methyl-L-homoseryl)amino)-2-methylpropyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl) propyl)carbamate LCMS: Anal. Calcd. for C 40 H 52 N 8 O 8 : 772; found: 773 (M+H) + .
  • Example B LCMS: Anal. Calcd. for C 16 H 21 BrN 3 O 2 : 366 found: 367 (M+H) + .
  • Example C LCMS: Anal. Calcd. for C 22 H 31 BN 3 O 4 :413 ; found: 414 (M+H) + .
  • Example D LCMS: Anal. Calcd. for C 37 H 40 N 6 O 4 : 632; found: 633 (M+H) + .
  • Example E LCMS: Anal. Calcd. for C 29 H 34 N 6 O 2 : 498 found: 499 (M+H) + .
  • Example F LCMS: Anal.
  • Example R26 LCMS Anal. Calcd. for C 38 H 48 N 8 O 6 : 712; found: 713 (M+H) + .
  • Example R27 LCMS Anal. Calcd. for C 38 F 48 N 8 O 8 : 744; found: 745 (M+H) + .
  • Example R28 LCMS Anal. Calcd. for C 34 H 40 N 8 O 6 : 756; found: 757 (M+H) + .
  • a single neck 50 mL flask equipped with a magnetic stirrer was charged with a compound from, Example (150 mg, 180 mmol) in Methanol (5 mL). To this solution was added a slurry of Palladium on carbon 10% (100 mg) in Methanol (2mL). The mixture was purged with 60 psi of Hydrogen. The mixture was shaked on a Parr overnight at room temperature. The contain of the reactor was analyzed by LC-MS and showed a 20% completion. A slurry of Palladium Hydroxide on carbon 20 % (100 mg) in Acetic acid (2 mL) was added. The mixture was purged with hydrogen and shake on a Parr shaker with 60 psi of Hydrogen over the weekend.
  • Example I Anal. Calcd. for C 42 H 50 BN 6 O 5 : 718 found: 719 (M+H) + .
  • Example J Anal. Calcd. for C 46 H 56 N 8 O 7 : 832; found: 833 (M+H) + .
  • Example R29 Anal. Calcd. for C 46 H 56 N 8 O 7 : 742 found: 743 (M+H) + .
  • Step 1 A solution of (S)-tert-butyl 2-(5-(4'-(2-acetamido-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (55.0 mg, 0.11 mmol) in CH 2 Cl 2 (5 mL) and TFA (1 mL) was allowed to stir at rt for 3 h. The reaction mixture was concentrated in vacuo to give the TFA salt of the title compound (55.0 mg) which was carried directly to the next step.
  • LCMS Anal. Calcd. for C 24 H 24 N 6 O: 412; found: 413 (M+H) + .
  • Step 2 The brown oil from Step 1 was suspended in 25% conc. HCl in MeOH (10 mL) and heated at reflux for 3h. The volatiles were removed under reduced pressure and the residue was purified by prep HPLC (CH 3 CN-H 2 O-TFA) to give the TFA salt of the title compound (20 mg, 42%).
  • LCMS Anal. Calcd. for C 22 H 22 N 6 : 370; found: 371 (M+H) + .
  • HCV Replion assay was utilized in the present disclosure, and was prepared, conducted and validated as described in commonly owned PCT/US2006/022197 and in O'Boyle et al. Antimicrob Agents Chemother. 2005 Apr;49(4):1346-53 .
  • HCV 1b-377-neo replicon cells were used to test the currently described compound series as well as cells resistant to compound A due to a Y2065H mutation in NS5A (described in application PCT/US2006/022197 ).
  • the compounds tested were determined to have more than 10-fold less inhibitory activity on cells resistant to compound A than wild-type cells indicating a related mechanism of action between the two compound series.
  • the compounds of the present disclosure can be effective to inhibit the function of the HCV NS5A protein and are understood to be as effective in combinations as previously described in application PCT/US2006/022197 and commonly owned WO/04014852 . Further, the compounds of the present disclosure can be effective against the HCV 1b genotype.
  • Table 2 shows the EC50 values of representative compounds of the present disclosure against the HCV 1b genotype.
  • compounds of the present disclosure are active against the 1a, 1b, 2a, 2b, 3a, 4a, and 5a genotypes.
  • the compounds of the present disclosure may inhibit HCV by mechanisms in addition to or other than NS5A inhibition.
  • the compounds of the present disclosure inhibit HCV replicon and in another embodiment the compounds of the present disclosure inhibit NS5A.
  • Table 2 Example Range R26 D R27 D R28 D R34 D R35 B R29 D R36 D R20 D R37 D R33 C
  • the compounds of the present disclosure may inhibit HCV by mechanisms in addition to or other than NS5A inhibition. In one embodiment the compounds of the present disclosure inhibit HCV replicon and in another embodiment the compounds of the present disclosure inhibit NS5A. Compounds of the present disclosure may inhibit multiple genotypes of HCV.

Claims (14)

  1. Composé sélectionné parmi
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1S)-2-méthyl-1,1-propanediyl)imino((2S)-1-oxo-1,2-propanediyle)));
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1S)-2-méthyl-1,1-propanediyl)imino((2S,3R)-3-méthoxy-1-oxo-1,2-butanediyle)));
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1S)-2-méthyl-1,1-propanediyl)imino((2S)-3-méthyl-1-oxo-1,2-butanediyle)));
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1S)-2-méthyl-1,1-propanediyl)imino((2S)-4-méthoxy-1-oxo-1,2-butanediyle)));
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1R)-2-méthyl-1,1-propanediyl)imino((2S)-3-méthyl-1-oxo-1,2-butanediyle)));
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1R)-2-méthyl-1,1-propanediyl)imino((2S)-1-oxo-1,2-propanediyle)));
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1R)-2-méthyl-1,1-propanediyl)imino((2S)-4-méthoxy-1-oxo-1,2-butanediyle)));
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1R)-2-méthyl-1,1-propanediyl)imino((2S,3R)-3-méthoxy-1-oxo-1,2-butanediyle)));
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1R)-2-méthyl-1,1-propanediyl)imino((2R)-3-méthyl-1-oxo-1,2-butanediyle)));
    biscarbamate de diméthyl-(4,4'-biphényldiylbis(1H-imidazole-4,2-diyl((1S)-2-méthyl-1,1-propanediyl)imino((2R)-3-méthyl-1-oxo-1,2-butanediyle)));
    N2-(méthoxycarbonyl)-N-((1S)-1-(4-(4'-(2-((2S)-1-(N-(méthoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphénylyl)-1H-imidazol-2-yl)-2-méthylpropyl)-L-valinamide;
    carbamate de méthyl-((1S,2R)-2-méthoxy-1-(((25)-2-(4-(4'-(2-((1S)-1-(N-méthoxycarbonyl)-O-méthyl-L-thréonyl)amino)-2-méthylpropyl)-1H-imidazol-4-yl)-4-biphénylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyle);
    carbamate de méthyl-((1S)-3-méthoxy-1-(((2S)-2-(4-(4'-(2-((1S)-1-(N-méthoxycarbonyl)-O-méthyl-L-homoséryl)amino)-2-méthylpropyl)-1H-imidazol-4-yl)-4-biphénylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyle);
    carbamate de méthyl-((1S)-2-((2S)-2-(4-(4'-(2-((1S)-1-(N-méthoxycarbonyl)-L-alanyl)amino)-2-méthylpropyl)-1H-imidazol-4-yl)-4-biphénylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-méthyl-2-oxoéthyle);
    N2-(méthoxycarbonyl)-N-((1R)-1-(4-(4'-(2-((2S)-1-(N-(méthoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphénylyl)-1H-imidazol-2-yl)-2-méthylpropyl)-L-valinamide;
    carbamate de methyl-((1S,2R)-2-méthoxy-1-(((2S)-2-(4-(4'-(2-((1R)-1-(N-méthoxycarbonyl)-O-méthyl-L-thréonyl)amino)-2-méthylpropyl)-1H-imidazol-4-yl)-4-biphénylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyle);
    carbamate de methyl-((1S)-3-méthoxy-1-(((2S)-2-(4-(4'-(2-((1R)-1-(N-méthoxycarbonyl)-O-méthyl-L-homoséryl)amino)-2-méthylpropyl)-1H-imidazol-4-yl)-4-biphénylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyle); et
    carbamate de méthyl-((1S)-2-((2S)-2-(4-(4'-(2-((1R)-1-(N-méthoxycarbonyl)-L-alanyl)amino)-2-méthylpropyl)-1H-imidazol-4-yl)-4-biphénylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-1-méthyl-2-oxoéthyle);
    ou un sel pharmaceutiquement acceptable de ceux-ci.
  2. Composé sélectionné parmi
    Figure imgb0078
    Figure imgb0079
    Figure imgb0080
    Figure imgb0081
    Figure imgb0082
    Figure imgb0083
    Figure imgb0084
     ou un sel pharmaceutiquement acceptable de ceux-ci.
  3. Composition comprenant un composé selon les revendications 1 ou 2 ou un sel pharmaceutiquement acceptable de ceux-ci et un véhicule pharmaceutiquement acceptable.
  4. Composition selon la revendication 3, comprenant en outre un ou deux composés supplémentaires ayant une activité anti-VHC.
  5. Composition selon la revendication 4, dans laquelle au moins l'un des composés supplémentaires est un interféron ou une ribavirine.
  6. Composition selon la revendication 5, dans laquelle l'interféron est sélectionné parmi l'interféron alpha 2B, l'interféron alpha pégylé, l'interféron consensus, l'interféron alpha 2A et l'interféron tau lymphoblastoïde.
  7. Composition selon la revendication 4, dans laquelle au moins l'un des composés supplémentaires est sélectionné parmi l'interleukine 2, l'interleukine 6, l'interleukine 12, un composé qui augmente le développement d'une réponse des cellules T auxiliaires de type 1, un ARN interférent, un ARN anti-sens, l'imiquimod, la ribavirine, un inhibiteur d'inosine 5'-monophosphate déshydrogénase, l'amantadine et la rimantadine.
  8. Composition selon la revendication 4, dans laquelle au moins l'un des composés supplémentaires est efficace pour inhiber la fonction d'une cible sélectionnée parmi la métalloprotéase du VHC, la sérine protéase du VHC, la polymérase du VHC, l'hélicase du VHC, la protéine NS4B du VHC, l'entrée du VHC, l'assemblage du VHC, la sortie du VHC, la protéine NS5A du VHC et l'IMPDH, dans le traitement d'une infection par le VHC.
  9. Composé selon les revendications 1 ou 2 ou un sel pharmaceutiquement acceptable de ceux-ci, à utiliser dans le traitement d'une infection par le VHC chez un patient.
  10. Composé à utiliser selon la revendication 9, comprenant en outre utiliser un ou deux composés supplémentaires ayant une activité anti-VHC, avant, après ou simultanément avec le composé selon les revendications 1 ou 2 ou un sel pharmaceutiquement acceptable de ceux-ci.
  11. Composé à utiliser selon la revendication 10, où au moins l'un des composés supplémentaires est un interféron ou une ribavirine.
  12. Composé à utiliser selon la revendication 11, où l'interféron est sélectionné parmi l'interféron alpha 2B, l'interféron alpha pégylé, l'interféron consensus, l'interféron alpha 2A et l'interféron tau lymphoblastoïde.
  13. Composé à utiliser selon la revendication 10, où au moins l'un des composés supplémentaires est sélectionné parmi l'interleukine 2, l'interleukine 6, l'interleukine 12, un composé au augmente le développement d'une réponse des cellules T auxiliaires de type 1, un ARN interférent, un ARN anti-sens, l'imiquimod, la ribavirine, un inhibiteur d'inosine 5'-monophosphate déshydrogénase, l'amantadine et la rimantadine.
  14. Composé à utiliser selon la revendication 10, où au moins l'un des composés supplémentaires est efficace pour inhiber la fonction d'une cible sélectionnée parmi la métalloprotéase du VHC, la sérine protéase du VHC, la polymérase du VHC, l'hélicase du VHC, la protéine NS4B du VHC, l'entrée du VHC, l'assemblage du VHC, la sortie du VHC, la protéine NS5A du VHC et l'IMPDH, dans le traitement d'une infection par le VHC.
EP08780411A 2008-02-12 2008-02-12 Inhibiteurs du virus de l'hépatite c Not-in-force EP2250163B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
SI200830675T SI2250163T1 (sl) 2008-02-12 2008-02-12 Hepatitis c virus inhibitorji
PL08780411T PL2250163T3 (pl) 2008-02-12 2008-02-12 Inhibitory wirusa zapalenia wątroby typu C
CY20121100523T CY1112848T1 (el) 2008-02-12 2012-06-08 Αναστολεις του ιου της ηπατιτιδας c

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2008/053638 WO2009102318A1 (fr) 2008-02-12 2008-02-12 Inhibiteurs du virus de l'hépatite c

Publications (2)

Publication Number Publication Date
EP2250163A1 EP2250163A1 (fr) 2010-11-17
EP2250163B1 true EP2250163B1 (fr) 2012-03-28

Family

ID=39944252

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08780411A Not-in-force EP2250163B1 (fr) 2008-02-12 2008-02-12 Inhibiteurs du virus de l'hépatite c

Country Status (22)

Country Link
EP (1) EP2250163B1 (fr)
JP (1) JP5314053B2 (fr)
KR (1) KR101468765B1 (fr)
CN (1) CN101998952B (fr)
AT (1) ATE551337T1 (fr)
AU (1) AU2008350327B2 (fr)
BR (1) BRPI0822335A2 (fr)
CA (1) CA2715367C (fr)
CY (1) CY1112848T1 (fr)
DK (1) DK2250163T3 (fr)
EA (1) EA018782B1 (fr)
ES (1) ES2383388T3 (fr)
HK (1) HK1144935A1 (fr)
HR (1) HRP20120440T1 (fr)
IL (1) IL207468A (fr)
MX (1) MX2010008650A (fr)
NZ (1) NZ587323A (fr)
PL (1) PL2250163T3 (fr)
PT (1) PT2250163E (fr)
SI (1) SI2250163T1 (fr)
WO (1) WO2009102318A1 (fr)
ZA (1) ZA201005700B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9073942B2 (en) 2012-02-10 2015-07-07 Lupin Limited Antiviral compounds with a heterotricycle moiety

Families Citing this family (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7906655B2 (en) 2008-08-07 2011-03-15 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8383094B2 (en) 2008-10-01 2013-02-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8541424B2 (en) 2008-12-23 2013-09-24 Abbott Laboratories Anti-viral compounds
EP2367823A1 (fr) 2008-12-23 2011-09-28 Abbott Laboratories Composés antiviraux
US8394968B2 (en) 2009-02-17 2013-03-12 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8188132B2 (en) 2009-02-17 2012-05-29 Enanta Pharmaceuticals, Inc. Linked dibenzimidazole derivatives
US8242156B2 (en) 2009-02-17 2012-08-14 Enanta Pharmaceuticals, Inc. Linked dibenzimidazole derivatives
TWI438200B (zh) 2009-02-17 2014-05-21 必治妥美雅史谷比公司 Ｃ型肝炎病毒抑制劑
US9765087B2 (en) 2009-02-27 2017-09-19 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
CA2753382C (fr) 2009-02-27 2014-12-23 Enanta Pharmaceuticals, Inc. Inhibiteurs du virus de l'hepatite c
US8101643B2 (en) 2009-02-27 2012-01-24 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
US8673954B2 (en) 2009-02-27 2014-03-18 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
US8507522B2 (en) 2009-03-06 2013-08-13 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8796466B2 (en) 2009-03-30 2014-08-05 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
TW201038559A (en) 2009-04-09 2010-11-01 Bristol Myers Squibb Co Hepatitis C virus inhibitors
US8143414B2 (en) 2009-04-13 2012-03-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010120935A1 (fr) 2009-04-15 2010-10-21 Abbott Laboratories Composés antiviraux
EA027493B1 (ru) 2009-05-13 2017-07-31 Джилид Фармассет Ллс Промежуточные соединения для получения противовирусного соединения
US8138215B2 (en) 2009-05-29 2012-03-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8211928B2 (en) 2009-05-29 2012-07-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8716454B2 (en) 2009-06-11 2014-05-06 Abbvie Inc. Solid compositions
US8937150B2 (en) 2009-06-11 2015-01-20 Abbvie Inc. Anti-viral compounds
US9394279B2 (en) 2009-06-11 2016-07-19 Abbvie Inc. Anti-viral compounds
DK2628481T3 (en) 2009-06-11 2016-06-06 Abbvie Bahamas Ltd Tri-substituted heterocycles AS INHIBITORS OF HEPATITIS C VIRUS (HCV) replication
US8221737B2 (en) 2009-06-16 2012-07-17 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8609648B2 (en) 2009-07-02 2013-12-17 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
WO2011009084A2 (fr) 2009-07-16 2011-01-20 Vertex Pharmaceuticals Incorporated Analogues du benzimidazole pour le traitement ou la prévention des infections à flavivirus
CA2768668A1 (fr) * 2009-07-23 2011-01-27 Shire Llc Promedicaments a base de l'acide amine galantamine et de peptides et utilisations de ceux-ci
US8344155B2 (en) 2009-09-04 2013-01-01 Glaxosmith Kline Llc Chemical compounds
US8815928B2 (en) 2009-09-11 2014-08-26 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8927709B2 (en) 2009-09-11 2015-01-06 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8759332B2 (en) 2009-09-11 2014-06-24 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8703938B2 (en) 2009-09-11 2014-04-22 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US9156818B2 (en) 2009-09-11 2015-10-13 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8822700B2 (en) 2009-09-11 2014-09-02 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
UA108211C2 (uk) 2009-11-04 2015-04-10 Янссен Рід Айрленд Бензімідазолімідазольні похідні
US20110274648A1 (en) 2009-11-11 2011-11-10 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110269956A1 (en) 2009-11-11 2011-11-03 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110281910A1 (en) 2009-11-12 2011-11-17 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
WO2011081918A1 (fr) 2009-12-14 2011-07-07 Enanta Pharmaceuticals, Inc Inhibiteurs du virus de l'hépatite c
US8377980B2 (en) 2009-12-16 2013-02-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2011075607A1 (fr) * 2009-12-18 2011-06-23 Intermune, Inc. Nouveaux inhibiteurs de la réplication du virus de l'hépatite c
EP2513113B1 (fr) 2009-12-18 2018-08-01 Idenix Pharmaceuticals LLC Inhibiteurs du virus de l'hépatite c à base de 5,5-arylène ou hétéroarylène condensé
US8362020B2 (en) 2009-12-30 2013-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2011091417A1 (fr) 2010-01-25 2011-07-28 Enanta Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
US8933110B2 (en) 2010-01-25 2015-01-13 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8623814B2 (en) 2010-02-23 2014-01-07 Enanta Pharmaceuticals, Inc. Antiviral agents
US8178531B2 (en) 2010-02-23 2012-05-15 Enanta Pharmaceuticals, Inc. Antiviral agents
MX2012010252A (es) 2010-03-04 2013-02-01 Enanta Pharm Inc Agentes farmaceuticos en combinacion como inhibidores de la replicacion del virus de hepatitis c (hcv).
EP2550267A1 (fr) 2010-03-24 2013-01-30 Vertex Pharmaceuticals Incorporated Analogues pour traiter ou prévenir les infections à flavivirus
EP2555622A4 (fr) 2010-04-09 2013-09-18 Enanta Pharm Inc Inhibiteurs du virus de l'hépatite c
WO2011146401A1 (fr) * 2010-05-17 2011-11-24 Intermune, Inc. Nouveaux inhibiteurs de la réplication du virus de l'hépatite c
EP2575819A4 (fr) 2010-06-04 2013-11-27 Enanta Pharm Inc Inhibiteurs du virus de l'hépatite c
WO2011154871A1 (fr) * 2010-06-10 2011-12-15 Pfizer Limited Inhibiteurs du virus de l'hépatite c
NZ605440A (en) 2010-06-10 2014-05-30 Abbvie Bahamas Ltd Solid compositions comprising an hcv inhibitor
JP2013529684A (ja) 2010-06-28 2013-07-22 バーテックス ファーマシューティカルズ インコーポレイテッド フラビウイルス感染の処置または予防のための化合物および方法
JP2013531011A (ja) 2010-06-28 2013-08-01 バーテックス ファーマシューティカルズ インコーポレイテッド フラビウイルス感染の処置または予防のための化合物および方法
US20130157894A1 (en) * 2010-07-16 2013-06-20 Jin-Hua Sun Methods to identify combinations of ns5a targeting compound that act synergistically to inhibit hepatitis c virus replication
WO2012021704A1 (fr) 2010-08-12 2012-02-16 Enanta Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
US20120195857A1 (en) * 2010-08-12 2012-08-02 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
MX2013001869A (es) 2010-08-17 2013-06-28 Vertex Pharma Compuestos y metodos para el tratamiento o prevencion de infecciones virales por flaviviridae.
US8859595B2 (en) 2010-08-26 2014-10-14 Rfs Pharma, Llc Potent and selective inhibitors of hepatitis C virus
AU2011305652B2 (en) 2010-09-22 2016-10-20 Janssen Biopharma, Inc. Azido nucleosides and nucleotide analogs
JP5891235B2 (ja) 2010-11-04 2016-03-22 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Ｃ型肝炎ウイルスの新規阻害剤
EP3699176A3 (fr) 2010-11-17 2020-11-18 Gilead Pharmasset LLC Composés antiviraux
WO2012087976A2 (fr) * 2010-12-21 2012-06-28 Intermune, Inc. Nouveaux inhibiteurs de la réplication du virus de l'hépatite c
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
CN103687489A (zh) 2011-05-18 2014-03-26 埃南塔制药公司 制备5-氮杂螺[2.4]庚烷-6-甲酸及其衍生物的方法
WO2013016499A1 (fr) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Procédés de préparation de composés du thiophène
AU2012286853A1 (en) 2011-07-26 2013-05-02 Vertex Pharmaceuticals Incorporated Thiophene compounds
WO2013021344A1 (fr) 2011-08-08 2013-02-14 Lupin Limited Nouveaux dérivés de quercétine utiles comme agents antiviraux
WO2013030750A1 (fr) 2011-09-01 2013-03-07 Lupin Limited Composés antiviraux
JP6073897B2 (ja) 2011-09-16 2017-02-01 ギリアド ファーマセット エルエルシー Ｈｃｖを処置するための方法
DK2907816T3 (en) 2011-11-16 2018-09-24 Gilead Pharmasset Llc CONDENSED IMIDAZOLYLIMIDAZOLES AS ANTIVIRAL COMPOUNDS
MX340033B (es) 2011-12-28 2016-06-21 Janssen Sciences Ireland Uc Derivados heterobiciclicos como inhibidores del virus de la hepatitis c.
US9034832B2 (en) 2011-12-29 2015-05-19 Abbvie Inc. Solid compositions
US9326973B2 (en) * 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2827876A4 (fr) 2012-03-22 2015-10-28 Alios Biopharma Inc Combinaisons pharmaceutiques comprenant un analogue thionucléotidique
US20130309196A1 (en) 2012-05-16 2013-11-21 Gilead Sciences, Inc. Antiviral compounds
BR112014011938B1 (pt) 2013-01-31 2021-03-16 Gilead Pharmasset Llc composição farmacêutica na forma de um comprimido com uma combinação de dose fixa de dois compostos antivirais, forma de dosagem farmacêutica compreendendo a referida composição e uso da referida composição
WO2014134251A1 (fr) 2013-02-28 2014-09-04 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques
US11484534B2 (en) 2013-03-14 2022-11-01 Abbvie Inc. Methods for treating HCV
US20150023913A1 (en) * 2013-07-02 2015-01-22 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20160158200A1 (en) * 2013-07-09 2016-06-09 Bristol-Myers Squibb Company Combinations of Hepatitis C Virus Inhibitors
EA201690473A1 (ru) 2013-08-27 2017-03-31 ГАЙЛИД ФАРМАССЕТ ЭлЭлСи Комбинированный состав двух противовирусных соединений
EP3089757A1 (fr) 2014-01-03 2016-11-09 AbbVie Inc. Formes galéniques antivirales solides
CN104860931A (zh) * 2014-02-21 2015-08-26 常州寅盛药业有限公司 丙肝病毒抑制剂及其制药用途
TWI721947B (zh) 2014-06-11 2021-03-21 美商基利法瑪席特有限責任公司 抗病毒化合物的固態形式
WO2016089814A1 (fr) 2014-12-02 2016-06-09 Concert Pharmaceuticals, Inc. Analogues deutériés du daclatasvir
US9790207B2 (en) * 2015-09-04 2017-10-17 Alexandre Vasilievich Ivachtchenko Pan-genomic inhibitors of NS5A protein encoded by HCV, pharmaceutical compositions, intermediates for inhibitor synthesis, and their synthesis and application methods
EP3891508A1 (fr) 2018-12-04 2021-10-13 Bristol-Myers Squibb Company Procédés d'analyse utilisant une courbe d'étalonnage dans un échantillon par surveillance de réaction d'isotopologues multiples
CN109456375B (zh) * 2018-12-11 2019-10-22 枣庄学院 一种抑制丙肝病毒的含单糖基杂环类化合物及制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003261434A1 (en) 2002-08-12 2004-02-25 Bristol-Myers Squibb Company Iminothiazolidinones as inhibitors of hcv replication
DE102004036971B4 (de) 2004-07-30 2009-07-30 Advanced Micro Devices, Inc., Sunnyvale Technik zur Bewertung lokaler elektrischer Eigenschaften in Halbleiterbauelementen
US8143288B2 (en) * 2005-06-06 2012-03-27 Bristol-Myers Squibb Company Inhibitors of HCV replication
US7659270B2 (en) * 2006-08-11 2010-02-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8329159B2 (en) * 2006-08-11 2012-12-11 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7759495B2 (en) * 2006-08-11 2010-07-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7741347B2 (en) * 2007-05-17 2010-06-22 Bristol-Myers Squibb Company Hepatitis C virus inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9073942B2 (en) 2012-02-10 2015-07-07 Lupin Limited Antiviral compounds with a heterotricycle moiety

Also Published As

Publication number Publication date
CN101998952B (zh) 2014-10-08
HRP20120440T1 (hr) 2012-06-30
IL207468A0 (en) 2010-12-30
KR20100114924A (ko) 2010-10-26
AU2008350327B2 (en) 2013-09-12
ATE551337T1 (de) 2012-04-15
JP5314053B2 (ja) 2013-10-16
PT2250163E (pt) 2012-06-01
SI2250163T1 (sl) 2012-08-31
MX2010008650A (es) 2010-08-30
WO2009102318A1 (fr) 2009-08-20
NZ587323A (en) 2012-02-24
EA018782B1 (ru) 2013-10-30
CA2715367A1 (fr) 2009-08-20
CY1112848T1 (el) 2016-02-10
EP2250163A1 (fr) 2010-11-17
JP2011511832A (ja) 2011-04-14
KR101468765B1 (ko) 2014-12-04
HK1144935A1 (en) 2011-03-18
BRPI0822335A2 (pt) 2019-09-24
PL2250163T3 (pl) 2012-10-31
ZA201005700B (en) 2012-01-25
CN101998952A (zh) 2011-03-30
ES2383388T3 (es) 2012-06-20
DK2250163T3 (da) 2012-07-16
IL207468A (en) 2015-11-30
AU2008350327A1 (en) 2009-08-20
EA201001276A1 (ru) 2011-04-29
CA2715367C (fr) 2015-05-05

Similar Documents

Publication Publication Date Title
EP2250163B1 (fr) Inhibiteurs du virus de l'hépatite c
EP2784075B1 (fr) Inhibiteurs du virus de l'hépatite C
EP2242752B1 (fr) Imidazolyle diphényle imidazoles inhibitrices du virus de l'hépatite c
EP2146984B1 (fr) Inhibiteurs du virus de l'hépatite c
US9776981B2 (en) Hepatitis C virus inhibitors
EP2049114B1 (fr) Inhibiteurs du virus de l'hépatite c
EP2300491B1 (fr) Inhibiteurs du virus de l hépatite c
AU2009214997B2 (en) Hepatitis C virus inhibitors
US8211928B2 (en) Hepatitis C virus inhibitors
US9006455B2 (en) Hepatitis C virus inhibitors
EP2242750B1 (fr) Dérivés de diphényle à restriction conformationnelle utilisés comme inhibiteurs du virus de l'hépatite c
EP2242751B1 (fr) Dérivés hétérocycliques inhibiteurs du virus de l'hépatite c
US20120195857A1 (en) Hepatitis C Virus Inhibitors
US20090285773A1 (en) Hepatitis C Virus Inhibitors
KR20090040910A (ko) Ｃ형 간염 바이러스 억제제
AU2012214767A1 (en) Hepatitis C virus inhibitors
US20160311806A1 (en) 4,4'-biphenyldiyl-bis-(1 h-imidazolyl) derivatives as hepatitis hcv inhibitors
US9775831B2 (en) Combinations comprising biphenyl derivatives for use in the treatment of HCV

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20100809

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

RIN1 Information on inventor provided before grant (corrected)

Inventor name: MARTEL, ALAIN

Inventor name: LAVOIE, RICO

Inventor name: LOPEZ, OMAR, D.

Inventor name: MEANWELL, NICHOLAS, A.

Inventor name: NGUYEN, VAN N.

Inventor name: ROMINE, JEFFREY, LEE

Inventor name: RUEDIGER, EDWARD, H.

Inventor name: LANGLEY, DAVID, R.

Inventor name: WANG, GAN

Inventor name: SNYDER, LAWRENCE, B.

Inventor name: HAMANN, LAWRENCE, G.

Inventor name: ST. LAURENT, DENIS, R.

Inventor name: YANG, FUKANG

Inventor name: BACHAND, CAROL

Inventor name: BELEMA, MAKONEN

Inventor name: DEON, DANIEL, H.

Inventor name: GOOD, ANDREW, C.

Inventor name: GOODRICH, JASON

Inventor name: JAMES, CLINT, A.

17Q First examination report despatched

Effective date: 20110117

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1144935

Country of ref document: HK

DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 551337

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120415

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: HR

Ref legal event code: TUEP

Ref document number: P20120440

Country of ref document: HR

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602008014480

Country of ref document: DE

Effective date: 20120524

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: MARKS & CLERK (LUXEMBOURG) LLP

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20120525

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2383388

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20120620

REG Reference to a national code

Ref country code: HR

Ref legal event code: T1PR

Ref document number: P20120440

Country of ref document: HR

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: NO

Ref legal event code: T2

Effective date: 20120328

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 11859

Country of ref document: SK

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E006747

Country of ref document: EE

Effective date: 20120626

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20120401442

Country of ref document: GR

Effective date: 20120713

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1144935

Country of ref document: HK

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20130103

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602008014480

Country of ref document: DE

Effective date: 20130103

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E015271

Country of ref document: HU

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20120440

Country of ref document: HR

Payment date: 20160115

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20160201

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: EE

Payment date: 20160119

Year of fee payment: 9

Ref country code: ES

Payment date: 20160113

Year of fee payment: 9

Ref country code: DE

Payment date: 20160209

Year of fee payment: 9

Ref country code: BG

Payment date: 20160108

Year of fee payment: 9

Ref country code: IS

Payment date: 20160105

Year of fee payment: 9

Ref country code: CZ

Payment date: 20160204

Year of fee payment: 9

Ref country code: CY

Payment date: 20160113

Year of fee payment: 9

Ref country code: IE

Payment date: 20160209

Year of fee payment: 9

Ref country code: CH

Payment date: 20160211

Year of fee payment: 9

Ref country code: DK

Payment date: 20160210

Year of fee payment: 9

Ref country code: LT

Payment date: 20160119

Year of fee payment: 9

Ref country code: NO

Payment date: 20160209

Year of fee payment: 9

Ref country code: TR

Payment date: 20160114

Year of fee payment: 9

Ref country code: MC

Payment date: 20160112

Year of fee payment: 9

Ref country code: SK

Payment date: 20160111

Year of fee payment: 9

Ref country code: IT

Payment date: 20160222

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20160125

Year of fee payment: 9

Ref country code: NL

Payment date: 20160210

Year of fee payment: 9

Ref country code: SE

Payment date: 20160211

Year of fee payment: 9

Ref country code: PT

Payment date: 20160211

Year of fee payment: 9

Ref country code: PL

Payment date: 20160203

Year of fee payment: 9

Ref country code: GR

Payment date: 20160114

Year of fee payment: 9

Ref country code: LV

Payment date: 20160205

Year of fee payment: 9

Ref country code: RO

Payment date: 20160107

Year of fee payment: 9

Ref country code: HU

Payment date: 20160114

Year of fee payment: 9

Ref country code: FI

Payment date: 20160209

Year of fee payment: 9

Ref country code: HR

Payment date: 20160115

Year of fee payment: 9

Ref country code: GB

Payment date: 20160210

Year of fee payment: 9

Ref country code: BE

Payment date: 20160113

Year of fee payment: 9

Ref country code: FR

Payment date: 20160108

Year of fee payment: 9

Ref country code: SI

Payment date: 20160122

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MT

Payment date: 20150218

Year of fee payment: 8

REG Reference to a national code

Ref country code: SE

Ref legal event code: RPOT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170228

REG Reference to a national code

Ref country code: HR

Ref legal event code: PBON

Ref document number: P20120440

Country of ref document: HR

Effective date: 20170212

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160229

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602008014480

Country of ref document: DE

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20170212

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E006747

Country of ref document: EE

Effective date: 20170228

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20170228

REG Reference to a national code

Ref country code: NO

Ref legal event code: MMEP

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170228

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20170301

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 551337

Country of ref document: AT

Kind code of ref document: T

Effective date: 20170212

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20170212

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170228

Ref country code: HR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

Ref country code: NO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170228

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170906

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170228

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170228

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

REG Reference to a national code

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 11859

Country of ref document: SK

Effective date: 20170212

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170213

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170814

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170213

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170213

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170829

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170301

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20171031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170228

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170228

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170901

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20171208

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20170228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20180705

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170213

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160212

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170903

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170212